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Vol. 301, Issue 3, 797-802, June 2002

Interaction of Human Organic Anion Transporters 2 and 4 with Organic Anion Transport Inhibitors

Atsushi Enomoto, Michio Takeda, Minoru Shimoda, Shinichi Narikawa, Yukari Kobayashi, Yasuna Kobayashi, Toshinori Yamamoto, Takashi Sekine, Seok Ho Cha, Toshimitsu Niwa and Hitoshi Endou

Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (M.T., S.N., Yu.K., T.S., S.H.C., H.E.); Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, Japan (A.E., T.N.); Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan (M.S.); and Department of Clinical Pharmacy, Showa University School of Pharmaceutical Sciences, Tokyo, Japan. (Ya.K., T.Y.)

The organic anion transport system is involved in the tubular excretion and reabsorption of various drugs and substances. The purpose of this study was to characterize the effects of various organic anion transport inhibitors on renal organic anion transport using proximal tubule cells stably expressing human organic anion transporter 2 (hOAT2) and hOAT4. Immunohistochemical analysis revealed that hOAT2 is localized to the basolateral side of the proximal tubule in the kidney. hOAT2 mediated a time- and concentration-dependent increase in prostaglandin F2alpha (PGF2alpha ) uptake. The organic anion transport inhibitors used for this study were probenecid, 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), betamipron, and cilastatin. Probenecid, but not KW-3902, betamipron, and cilastatin, significantly inhibited hOAT2-mediated PGF2alpha uptake. In contrast, probenecid, KW-3902, and betamipron, but not cilastatin, inhibited hOAT4-mediated estrone sulfate (ES) uptake. Kinetic analyses revealed that these inhibitions were competitive. The Ki value of probenecid for hOAT2 was 766 µM, whereas those of probenecid, KW-3902, and betamipron for hOAT4 were 54.9, 20.7, and 502 µM, respectively. These results suggest that probenecid, KW-3902, and betamipron could inhibit hOAT4-mediated ES uptake in vitro, whereas probenecid alone could inhibit the hOAT2-mediated PGF2alpha uptake. Comparing the Ki values with the therapeutically relevant concentrations of unbound inhibitors in the plasma, probenecid alone was predicted to inhibit hOAT4-mediated organic anion transport in vivo.

0022-3565/02/3013-0797$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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